Really,  seems that the transformation might be come from areas of dysplasia in the context of liver cell adenoma. In fact, liver adenoma can regress, while dysplasia is an irreversible,  premalignant change and will eventually progress to hepatocellular carcinoma   ^{(104,105,106)}.

It is generally believed that focal nodular hyperplasia (FNH) having a wider age distribution, is not associated with the use of oral contraceptives ^(107,108).  However,  a large proportion of women with FNH (50-75%)  are HC users,  as previous clinical observations affirmed ⁽¹⁰⁹⁾. 

However,in long-term HC users it was emphasized the need of surveillance with ultrasonography. It is known that sex hormones and anabolic –androgenic steroids are implicated in the development and progression of hepatic adenomas. 

The human liver expresses estrogen and androgen receptors and, experimentally both androgens and estrogens have been implicated in stimulating hepatocyte proliferation and may act as liver tumor inducers or promoters.  In humans,  receptors are present and may mediate the action of sex steroids or androgenic steroids on hepatic adenomas and adiacent liver,but in less than one third of patients. This evidence may have theraepeutic implications ^(110,111).

A paradigmatic case of liver adenoma in a young women affected from Polycystic ovary syndrome associated with high levels of androgen and following a high dose hormonal therapy has been reported ⁽¹¹²⁾.  So,surveillance can be advised also for women with hormonal imbalance treated with high doses of hormonal therapy.

However, the increased risk for hepatocellular carcinoma in the absence of hepatitis B viruses, is the only established evidence of a direct association between HC use and cancer risk,which led an International Agency for Research on Cancer Working Group to classify combined hormonal contraceptives as carcinogenic to humans in 1998 ⁽¹¹³⁾.  The role of estrogens in the genesis of hepatic adenomas is well established, but is more controversial with focal nodular hyperplasia ^(108,109). 

The appearance of low-dose HCs does not seem to have decreased the incidence of benign liver tumors. Therefore,  several studies have demonstrated that the risk of adenoma increase with the duration of treatment.

In the mean time. benign liver tumors are very rare and should not affect prescription of HCs.  Focal nodular hyperplasia of liver is less dangerous than hepatic adenomas but still necessitate stopping use. This pathological entity had been reported in women prior to widespread use of the pill,but HCs use appear to favor its growth.  Some cases of subhepatic vein thrombosis or the Budd-Chiari syndrome, associated to focal nodular hyperplasia as well as adenoma have been reported ^{(114, 115,116)}.

—
Rosa Sabatini and Giuseppe Loverro
Dept. Obstetrics and Gynecology,
General Hospital Policlinico-University of Bari, Italy
—

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